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Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same

a technology of fumagillol and derivatives, which is applied in the field of fumagillol derivatives, can solve the problems of chemical stability, toxicity, and few possibilities of tolerance occurring, and achieve the effects of improving toxicity and chemical stability

Inactive Publication Date: 2010-03-04
CHONG KUN DANG PHARMA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0077]Since a compound of the Chemical Formula 1 or salts thereof has excellent angiogenesis-inhibiting effect, they can be used as an anticancer drugs or an inhibitor for a cancer metastasis, or as a therapeutic agent for treating rheumatic arthritis, psoriasis, diabetic retinitis and obesity.

Problems solved by technology

In other word, there are few possibilities that the problem of tolerance will occur since an angiogenesis inhibitor does not directly act on tumor cells, but acts on endotherial cells of a living organism.
Although there is the strong point in which the angiogenesis inhibiting action of the above mentioned fumagillol derivative is excellent, there were problems that had to be improved with toxicity, chemical stability and solubility.

Method used

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  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same
  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same
  • Fumagillol derivatives or method for preparation of fumagillol derivatives, and pharmaceutical compositions comprising the same

Examples

Experimental program
Comparison scheme
Effect test

example 2

A preparation of O-(3,5-dimethoxy-4-(2-hydroxyethoxy)cinnamoyl)fumagillol

Step 1: A preparation of O-(4-acetoxy-3,5-dimethoxycinnamoyl)fumagillol

[0091]The same procedure as described in the Step 1 of the Example 1 was repeated, but using a compound of the Chemical Formula 2 (1.0 g), 4-acetoxy-3,5-dimethoxycinnamic acid (2.36 g), thionylchloride (1.29 ml), toluene (20 ml), sodium hydride (850 mg) and dimethylformamide (20 ml), to give 1.36 g (72%) of the title compound as a white solid.

[0092]1H-NMR (400 MHz, CDCl3) δ: 7.59 (d, 1H, J=16 Hz), 6.77 (s, 2H), 6.44 (d, 1H, J=16 Hz), 5.71 (m, 1H), 5.21 (m, 1H), 3.86 (s, 3H), 3.71 (dd, 1H, J=11, 2.7 Hz), 3.45 (s, 3H), 3.0 (d, 1H, J=4.0 Hz), 2.62 (t, 1H, J=6.4 Hz), 2.57 (d, 1H, J=4.0 Hz), 2.36 (m, 1H), 2.34 (s, 3H), 2.20-2.04 (m, 4H), 1.89 (m, 1H), 1.74 (s, 3H), 1.65 (s, 3H), 1.23 (s, 3H), 1.10 (m, 1H).

Step 2: A preparation of O-(3,5-dimethoxy-4-hydroxycinnamoyl)fumagillol

[0093]The same procedure as described in the step 2 of the Example 1 was...

example 3

A preparation of O-(4-(2-hydroxyethoxy)-3-methoxycinnamoyl)fumagillol

Step 1: A preparation of O-(4-acetoxy-3-methoxycinnamoyl)fumagillol

[0097]The sane procedure as described in the step 1 of Example 1 was repeated but using a compound of the Chemical Formula 2 (1.0 g), 4-acetoxy-3-methoxycinnamic acid (2.09 g), thionylchloride (1.29 ml), toluene (20 ml), triethylamine (2.7 ml) and dichloromethane (20 ml), to give 1.0 g (56%) of the title compound as light yellow syrub.

[0098]1H-NMR (400 MHz, CDCl3) δ: 7.62 (d, 1H, J=16 Hz), 7.13-7.03 (m, 3H), 6.44 (d, 1H, J=16 Hz), 5.73 (m, 1H), 5.43 (m, 1H), 5.21 (m, 1H), 3.88 (s, 3H), 3.71 (dd, 1H, J=11.2, 2.8 Hz), 3.45 (s, 3H), 3.00 (d, 1H, J=4 Hz), 2.62 (t, 1H, J=6.3 Hz), 2.57 (d, 1H, J=4 Hz), 2.35 (m, 1H), 2.32 (s, 3H), 2.20-2.04 (m, 4H), 1.89 (m, 1H), 1.74 (s, 3H), 1.65 (s, 3H), 1.23 (s, 3H), 1.11 (m, 1H).

Step 2: A preparation of O-(4-hydroxy-3-methoxycinnamoyl)fumagillol

[0099]The same procedure as described in the step 2 of Example 1 was repea...

example 4

A preparation of O-(3-(2-hydroxyethoxy)-4-methoxycinnamoyl)fumagillol

Step 1: A preparation of O-(3-acetoxy-4-methoxycinnamoyl)fumagillol

[0103]The same procedure as described in the step 1 of Example 1 was repeated but using a compound of the Chemical Formula 2 (1.0 g), 3-acetoxy-4-methoxycinnamic acid (2.09 g), thionylchloride (1.29 ml), toluene (20 ml), triethylamine (2.7 ml) and dichloromethane (20 ml), to give 1.01 g (59%) of the title compound as white solid.

[0104]1H-NMR (400 MHz, CDCl3) δ: 7.58 (d, 1H, J=16 Hz), 7.73 (m, 1H), 7.23 (m, 1H), 6.96 (d, 1H, J=8.5 Hz), 6.34 (d, 1H, J=16 Hz), 5.72 (m, 1H), 5.21 (m, 1H), 3.86 (s, 3H), 3.70 (dd, 1H, J=11, 2.7 Hz), 3.45 (s, 3H), 3.04 (d, 1H, J=4 Hz), 2.61 (t, 1H, J=6.3 Hz), 2.56 (d, 1H, J=4 Hz), 2.35 (m, 1H), 2.19-2.01 (m, 4H), 1.88 (m, 1H), 1.74 (s, 3H), 1.66 (s, 3H), 1.23 (s, 3H), 1.12 (m, 1H).

Step 2: A preparation of O-(3-hydroxy-4-methoxycinnamoyl)fumagillol

[0105]The same procedure as described in the step 2 of Example 1 was repeated...

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Abstract

The present invention relates to a fumagillol derivative, pharmaceutically acceptable salts thereof and a method for preparing the same. The compounds of the present invention can be prepared through acylation, hydrolysis and alkylation. The compound of the present invention can be prepared in the form of a pharmaceutically acceptable salt or inclusion compound. The present invention provides fumagillol derivatives having the following characteristics: increased inhibiting effect on angiogenesis, low toxicity, excellent solubility and chemical stability as compared to conventional angiogenesis inhibitors. The compounds of the present invention can be used as an anti-cancer medicine, inhibitor of cancer metastasis, or the therapeutic agent for treating rheumatic arthritis, psoriasis, diabetic retinitis or obesity.

Description

TECHNICAL FIELD[0001]The present invention relates to a fumagillol derivative or a method for preparation thereof, and pharmaceutical compositions comprising the same.BACKGROUND ART[0002]Angiogenesis is a phenomenon of generating new capillary vessels, which is one of the pathological phenomena happened in various diseases as well as one of normal physiological actions.[0003]Additionally, Angiogenesis has a deep connection with growth and metastasis of solid cancer, rheumatic arthritis, diabetic retinopathy, psoriasis, or the like [Billington, D.C. Drug Design and Discovery, (1991), 8, 3.], and the compounds inhibiting angiogenesis show the effect of treatment for obesity [J. Folkman, PNAS, (2002), 99, 10730˜10735].[0004]The compounds inhibiting angiogenesis have been developed and reported through many researches. Recently, as the clinical importance of therapeutic agents by means of controlling angiogenesis has been emphasized, researches on angiogenesis have increased. According ...

Claims

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Application Information

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IPC IPC(8): A61K31/336C07D305/14A61P35/00
CPCC07D303/28A61P17/06A61P19/02A61P27/02A61P3/04A61P35/00A61P35/04
Inventor LEE, SANG JOONAHN, SOON KILLEE, HONG WOOAHN, JOONG BOKSHIN, JAE SOOKWON, YOUNG MIN
Owner CHONG KUN DANG PHARMA CORP
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